We propose that responses to noxious stimulation of peripheral receptive fields are due to a complex interaction of serotonergic, adrenergic and cholinergic neuronal systems in the midbrain and brain stem. Furthermore, we have outlined possible sites of action at which opiate analgesics may modify the interactions among these neuronal systems. These systems will be examined by: (1) testing the response to noxious stimulation, opiate analgesics and analgesia-producing cholinergic drugs in animals with lesions in the n. raphe magnus or locus coeruleus; (2) stimulation of these nuclei to determine their influence on pain and opiate analgesia; (3) stimulating the locus coeruleus and ascertaining the effects in raphe magnus cells and spinal dorsal horn cells; (4) stimulating the raphe magnus and testing the effects on the transmission of pain impulses into the spinal cord; (5) testing the reactivity of raphe magnus cells to noxious stimuli and putative neurotransmitters.